Process for the preparation of 21-bromo steroids



United States Patent PRocEss FOR THE PREPARATION 0F ZI-BROMO STEROIDS NoDrawing. Application June 7, 1957 Serial No. 664,170

Claims priority, application Great Britain August 3, 1954 8 Claims. (Cl.260-39745) This invention is concerned with the preparation of steroidcompounds, and more particularly with an improved method for thebromination in the 21-position of 3 3:l7a-dihydroxy-11:20-diketoderivatives of pregnane or allopregnane.

The preparation of 2l-bromo-3fi:17a-dihydroxy-5apregnane-11:20-dione bythe bromination of 3,3:17a-dihydroxy-5a-pregnan-l1:20-dione isdescribed, in outline, by Chemerda, Chamberlin, Wilson and Tishler (J.A. C. S. 1951, 73, 4052) and by Rosenkranz, Pataki and Djerassi (ibid,p. 4055). A more detailed description incorporating the experimentaldetails, is given by Pataki, Rosenkranz and Djerassi (J. A. C. S., 1952,74, 5615), according to which an 0.3% solution in cholorform of 3/3:l7a-dihydroxy-5a-pregnan-11:20-dione is treated with bromine inchloroform. After suitable washing with sodium bicarbonate solution andwater the solvent is removed and the residue triturated with ether. Theyield is 65% of the theoretical if the assumption is made that theproduct is 100% pure.

This assumption as to the purity of the brominated product is, however,untrue for if this latter product is treated with sodium iodide inacetone and then with po tassium bicarbonate in acetic 'acid in order togive 21- acetoxy-3B:17u-dihydroxy-5a-pregnan-11:20-dione, M. P. 235-7"C., [cel +66 (acetone) it has been found that the material so obtainedis not pure being a mixture of the desired acetoxy compound withunbrominated materials thus indicating that the brominated productconsisted of the desired 21-bromo-3B:l7a-dihydroxy-5apregnan-l 1:ZO-dione and unchanged starting material. In general brominationscarried out in the manner described above lead to products that aremixtures, and it is thus desirable to employ a method which gives aconsistent product with as high a proportion of the desired compound aspossible. A further problem which arises is that the solubility of thestarting material (3,8:l7a-dihydroxy-llzZO-diketo derivatives ofpregnane and allopregnane) is so low in chloroform that inconcentrations above 0.3% the br'omination must be carried out with thestarting material in suspension.

It has now been found that the bromination of the3B:17a-dihydroxy-l1:ZO-diketo derivatives of pregnane or allo-pregnanemay be advantageously carried out by first forming a complex between thestarting material and hydrogen bromide or hydrogen chloride in an inert,relatively non-polar organic solvent containing a small amount of aprimary or secondary alcohol and then brominating this complex.

It has previously been proposed in U. S. Patent No. 2,684,375 to Olivetoto brominate keto-steroids, particularly Sfl-dihydrocortisone acetate,in the presence of a strong mineral acid, such as hydrobromic acid and asolvent medium comprising a tertiary alcohol and an inert solvent suchas chloroform or methylene chloride. The

Oliveto process is directed to bromination in the nucleus 2,861,089Patented Nov. 18, 1958 ice and it is to be noted that it uses thetertiary alcohol and inert solvent in equal proportions.

If one attempts to apply the Oliveto process to the sidechainbromination of 3,8:l7a-dihydroxy-11:ZO-diketo derivatives of pregnaneand allopregnane the reaction proceeds sluggishly in poor yields and nonuniform products are obtained. The process according to the inventionusing small proportions of primary or secondary alcoholic proceedshowever in good yield and substantially uniform products areobtained.

According to the present invention, therefore there is provided aprocess for the bromination in the 21-position of the3n:l7a-dihydroxy-ll:2'0-diketo derivatives of pregnane and allo-pregnaneconsisting of reacting said diketo derivative with a hydrogen halideselected from the group consisting of hydrogen bromide and hydrogenchloride in the presence of a substantially non-polar organic solventcontaining from 0.5 to 10% weight/volume (metric scale) of an alcoholselected from the group consisting of C -C aliphatic primary alcoholsand C -C aliphatic secondary. alcohols and brominating the result; inghydrogen halide complex.

Although the present process proceeds readily in good yield usingsecondary alcohols it is not, in general, so effective as when a primaryalcohol is used and hence I prefer to use primary alcohols.

It is further preferred to carry out the process according to theinvention on the said allo-pregnane derivative.

Suitable inert, substantially non-polar organic solvents for use in thepresent process are, for example, halogenated hydrocarbons, such ascholorform, methylene chloride, tetrachloroethane and carbontetrachloride, and nonpolar hydrocarbon solvents, such as benzene andpetroleum. Of these solvents I prefer chloroform, methylene chloride andtetrachloroethane. Examples of solvents which are not suit-able,becausethey tend to be brominated and are thus not inert, are unsaturatedcompounds, ether and acetonitrile.

By the expression substantially as applied to the non polar organicsolvents I mean that the non-polar organic solvent should be non-polarwhen considered in relation to the organic alcohol present in thenon-polar organic solvent.

.The inert, substantially non-polar solvents should contain from 05-10%weight/volume advantageously -1.0 3.0% weight/volume of the aliphaticalcohol, for example, ethanol.

proportion of ethanol, and this commercial material may be used withoutthe addition of further alcohol. The-resulting hydrogen halide complexis then treated with bromine; where pure starting material is usedsubstantially only the theoretical quantity of bromine is preferably,

added, whilst with impure starting material the use of. a slight excessover the theoretical quantity is preferred.

The bromination step is preferably carried out in suspen-' sion. Thisnot only leads to economy of solvent medium but also gives superioryields.

The product may, for example, be isolated by adding room temperature. Y

The 21-bromo compounds obtained by the process according to theinvention may be converted into the corresponding '21-esters, inparticular the 21-acetates, in any convenient manner, for example bytreatment of the bromo compound with the potassium salt of 'theappropriate acid,.for example, potassium acetate, as; described.

in'Examples 2, 3, 4, 5 and 6 which follow,

It will be appreciated that commerciallyavailable chloroform is normallystabilized with a small -In order that the invention may be wellunderstood the following examples are given by way of illustration only:1.7

Exarnple 1 tion, washed with ether (0.5 l.) and air-dried. There isobtained in this way 155 g. of crude21-bI0m0-3fitl7udihydroxy5a-pregnan-l1:20-dione' (containing someunchanged 3p:17u-dihydroxy-5a-pregnan-1l:20-dione) suitable forconversion to the 21-acetoxy compound.

Example '2 3 S:17a-dihydroxy-5a-pregnan-l1:20-dione (500 g.) issuspended in chloroform (7.5 1.; 1.4% alcohol w./v.)

containing hydrogen chloride (52.5 g.) and the mixture stirred at roomtemperature for 5 minutes. With continued vigorous stirring a solutionof bromine (230 g.)

in chloroform (2.5 l.) is added at such a rate that a slight excess ofbromine is maintained in the suspension. Total time of addition 50minutes. added with stirring, and the suspended solid is collected byfiltration, washed with ether (2 l.) and air-dried. There is obtained inthis way 628 g. of crude 2l-bromo-3,6:17a-dihydroxy-5a-pregnan-11:20-dione. A second crop is obtained bywashing the combined mother liquors twice with water (5 1. each time) toremove hydrogen halides and evaporating to dryness in vacuo on the steambath. The residue is leached with acetone (0.2 l.) and the residualsolid filtered off to give 20 g. of 2l-bromide after air drying.

The combined crops of bromo-compound (648 g.) are suspended in acetone(12.5 1.) with anhydrous potassium acetate (800 g.) and'the mixturerefluxed with mechanical stirring for 1 hour. The inorganic salts arefiltered oil? and washed with acetone (1 1.). The com bined filtrate andwashings are concentrated by distillation on a steam bath to a volume ofapproximately 800 ml. Water (12.1) is added, and after thorough mix ing,the suspension is filtered, the solid product being well washed withwater and dried at 80 C. There is obtained in this manner 541g. of crude21-acetoxy- 3,3:170; dihydroxy 5w pregnan 11:20 dione, M. P. 229-232(assay by infra-red 94%).

Crystallisation from methanol (5.5 l.) and drying the Ether (7.5 l.) is

evaporating to dryness in vacuo andleaching with acetone.

The combined crops of bromo-compound (13.2 g.)

are converted to 21-acetoxy-348:l7a-dihydroxy-5a-pregnan-11:20-dione bytreatment with anhydrous potassium acetate (15 g.) in refluxing acetone(200 ml.) for one hour. There is isolated 1L0 giof crude 21-acetate M.P. 224-227 (assay by infra-red 96%). Purification bytreatment'withGira'rd reagent P affords 10.04 g. of purified 21-acetateM. P. 23 l-235 (assay by infra-red 98%).

. Example 4 3,8:17a-dihydroxy-5u-prcgnan-11:20'dione (100 g.) issuspended in methylene chloride (1.4 l.) and 8.5 N hydrogen chloride inethanol (37.6 ml.) is added with stirring at room temperature. Withcontinued stirring a solution of bromine (15.4 ml.) in methylenechloride (500 ml.) is added over a period of 26 minutes. .The

solid is filtered ofi, washedwith ether (500 ml.) and airdried.. Thereis obtained inthis way 100.2 g. of crude 2'1 -'bromo 318:1701 dihydroxy5a pregnan 11:20- dione. A 'second crop of 11.5 g. is obtained bycombining the mother liquors and the ether wash, washing with water,evaporating to dryness in vacuo and leaching with acetone.

The combined crops of bromo-compound (111.7 g.) are. converted to2l-acetoxy-3fi:l7u-dihydroxy-5a-pregnan-11:20-dione as described inExample 2. Thereis isolated 95.5 g. of crude 21-acetate (M. P. 220224C.). Purification by treatment with Girard reagent P afiords 69.4 g. ofpurified 2l-acetate M. P. 237-241" C. (assay by infra-red 98%).

ExampleS 3B:17a-dihydroxy-5a--pregnane-11:20-dione (10 g.) is suspendedin petroleum ether 150 ml. B. P. 80/ 100 previously washed withconcentrated sulphuric acid followed by water, dried, distilled and thensaturated with industrial methylated spirit). Hydrogen chloride gas isblown into the well stirred suspension until no more is absorbed. Asolution of bromine in purified petroleum ether (46.5 ml. of 1.24 N) isadded dropwise as fast as the bromine colour is discharged. Thesuper-natant petrol is poured off from the resulting gum which is thentrituratcd with acetone ml.) and ether (50 ml.) to give a reddish solid.There is obtained in this manner 7.8 g. of crude21-bromo-3fi:17a-dihydroxy-5a-pregnanell:20dione.

crystalline lproduct'in vacuo at l20 gives 411 'g. of

- 3,8: 17a-dihydroxy-5e-pregnan-1I :ZO-dione ('10.g) is suspended intetrachloroethane (150 ml.) and 5 N hydrogen chloride in ethanol (6.2ml.) is added with stirring at room temperature. With continued vigorousstirring a solution of bromide in tetrachloroethane (40.2 ml. of 1.42N). is added over a period of 17 minutes. .The suspended solid iscollected by filtration, washed with ether (100"ml.) and air-dried.There is obtained in this way 11.55 g. of crudeZI-bromofi:17u-dihydroxy-,

5a-pregnan-llz20rdione. A second crop of 1.65 g.'.is obtained by washingthe .mother liquors with water,

By treatment with dry potassium acetate in refluxing acetone followed byisolation and purification the bromo compound may be converted into 3.4g. of 21-acetoxy- 313:l7a-dihydroxy-5a-pregnane-l1:20-dione, M. P. 231-234 (assay by infra-red 98%).

Example 6 3p:17a-dihydroxy-5a-pregnane-ll:20-dione (10 g.) is suspendedin benzene (150 ml.) and 5 N hydrogen chloride in ethanol (6.2 ml.)added. The suspension is vigorously stirred and a solution of bromine inbenzene (44.5 ml. of 1.29 N) is added dropwise as fast as the brominecolour is discharged. The suspended solid is collected, washed with alittle ether and air-dried. There is thus obtained 11.2 g. of crude2l-bromo-3fizl7a-dihydroxy-su-pregnane-ll:20-dione suitable forconversion to 21-acetoxy3p:17a-dihydroxy-Su-pregnane-11:20 dione.

The bromo-compound 11.2 g. is refluxed in acetone (200 ml.) with drypotassium acetate (15 g.) for one hour. Inorganic salts are filteredoflF, washed with a little acetone and the combinedacetone filtrates areconcentrated in vacuo to 50 ml. Water (500 ml.) is added, theprecipitated. solid collected, washed with water and dried at There isobtained in this way 8.8 g. of crude 21 acetoxy 3,5:l7adihydroxy-5u-pregnane-11:20- dione M. P. 221-224 (assay by infra-redUsing a similar'reaction technique to that adopted in I; the foregoingexamples, 3 8:17u-dihydroxy-5tat-pregnanc- 11:20-dime S .brominated inchloroform containing various primary and secondary alcohols. Theresults obtained are as follows:

non-polar solvent is an unsubstituted hydrocarbon.

Weight Yield of of Addition to chloroform Remarks on Bro- 2l-bromo Yieldof pure Example No. Starting (150 ml. used) mination com- Yield of crude21-Acetate 21-Acetate material, pound,

grams grams 10.0 2% ethanol Cut-ofi in 25 mins. 12. 19 10.45 g notobtained. 10.0 o Cut-offin20 mins. 11.35 9.90 D0. 10.0 0.4% ethanolComplete uptake in 12. 42 10.

1 our. 10. 0 2% methanoL. Cut-oil in 20 mins. 11. 71 10. l0. 0 2%n-propanol Cut-off in 45 mins. 11. 81 10. 10. 0 2% n-butanol. (lllut-ofiin 1% 11. 50 10.

ours. 10.0 do Cut-off in 15 mins- 11. 50 9.80 not obtained. 10.0 2%n-amyl alcoho1 Cutoff in 23 mins. 10. 31 9.0 Do. 10.0 2% iso-amylalcohol Cut-oft in 25 mins. 11. 48 9.7 Do. 10. 0 2% n-octanol Out-oft in22 mius. 12. 10.33 Do. 10.0 2% iso-propyl alcohoL- Oogjpklete uptake in9. 72 2.06 g.; 17-OH, 6.75 g"... 3.88 g.

2 2 ours. 10.0 2% sec-butanol Compllete uptake in 9. 90 0.40 g.; 17-OH,7.15 g 4.23 g

1 2 ours. 10. 0 2% cyclo'hexanol conliplete uptake in 9. 2.0 g.; 17-OH,5.85 g 3.42 g.

1 our.

This application is a continuation-in-part of copending applicationSerial No. 522,852, filed July 18, 1955, now abandoned.

I claim:

1. A process for the bromination in the 21-position of the313:l7a-dihydroxy-ll:ZO-diketo derivatives of pregnane and allo-pregnaneconsisting of reacting said diketo derivative with a hydrogen halideselected from the group consisting of hydrogen bromide and hydrogenchloride in the presence of a substantially non-polar organic solventcontaining from 0.5 to 10% weight/volume of an alcohol selected from thegroup consisting of C -C aliphatic primary alcohols and C -C aliphaticsecondary alcohols and brominating the resulting hydrogen halidecomplex.

2. The process of claim 1 in which said aliphatic primary alcohol isethanol.

3. The process of claim 2 in which said substantially non-polar solventcontains from 1.0 to 3.0% weight/ volume of ethanol.

4. The process of claim 2 in which said substantially non-polar solventis a halogenated hydrocarbon.

6. The process of claim 2 in which the reaction is carried out at atemperature between 10 and 35 C.

7. The process of claim 2 in which the starting material is suspended insaid substantially non-polar solvent.

8. A process for the bromination in the 21-position of 3B:17u-dihydroxy-5a-pregnane-11:20-dione consisting of reacting saidcompound with a hydrogen halide selected from the group consisting ofhydrogen bromide and hydrogen chloride in the presence of an organicsolvent selected from the group consisting of chloroform, methylenedichloride and tetrachloroethane containing from 1.0 to 3.0%weight/volume of a C -C primary alkanol and brominating the resultinghydrogen halide complex in suspension in said organic solvent at atemperature of 10-35 C.

References Cited in the file of this patent UNITED STATES PATENTS2,752,339 Julian et al June 26, 1956

1. A PROCESS FOR THE BROMINATION IN THE 21-POSITION OF THE 3B:17A-DIHYDROXY-11:20-DIKETO DERIVATIVES OF PREGNANE AND ALLO-PREGNANE CONSISTING OF REACTING SAID DIKETO DERIVATIVE WITH A HYDROGEN HALIDE SELECTED FROM THE GROUP CONSISTING OF HYDROGEN BROMIDE AND HYDROGEN CHLORIDE IN THE PRESENCE OF A SUBSTANTIALLY NON-POLAR ORGANIC SOLVENT CONTAINING FROM 0.5 TO 10% WEIGHT/VOLUME OF AN ALCOHOL SELECTED FROM THE GROUP CONSISTING OF C1-C3 ALIPHATIC PRIMARY ALCOHOLS AND C1-C6 ALIPHATIC SECONDARY ALCOHOLS AND BROMINATING THE RESULTING HYDROGEN HALIDE COMPLEX. 